Methods of Using Low Dose Naltrexone to Treat Chronic Pain

ABSTRACT

Methods of using low dose naltrexone to treat chronic pain in a patient. The methods of using low dose naltrexone to treat chronic pain generally includes administering to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent.

CROSS REFERENCE TO RELATED APPLICATIONS

I hereby claim benefit under Title 35, United States Code, Section119(e) of U.S. provisional patent application Ser. No. 63/132,628 filedDec. 31, 2020 (Docket No. SOIN-002). The 63/132,628 application iscurrently pending. The 63/132,628 application is hereby incorporated byreference into this application.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable to this application.

BACKGROUND

The described example embodiments in general relate to various methodsof using low dose naltrexone to treat chronic pain in a patient.

Complex regional pain syndrome (CRPS) is a chronic neurologicalcondition that can cause severe pain. CRPS is a rare, orphan chronicpain disorder affecting fewer than 200,000 individuals each year and isa rare or orphan disease. The characteristic feature of CRPS ishypersensitivity to stimulus resulting in pain, including allodynia,pain due to a stimulus that does not usually provoke pain, andhyperalgesia, increased pain from a stimulus that usually provokes pain.CRPS is a neuroinflammatory condition and patients frequently experienceautonomic, sensory, vasomotor, and motor dysfunction (such as pain intheir limbs and dystonia).

CRPS is divided into two categories. CRPS Type 1 (also known as reflexsympathetic dystrophy or RSD) occurs in the absence of confirmed nerveinjury. CRPS Type 2 (previously known as causalgia) occurs withconfirmed nerve injury.

The cause of CRPS is likely multifactorial and the exact mechanism isstill unclear. However, evidence suggests that Toll-like receptors(TLR4) and inflammatory cytokines play key roles in the mechanisticpathway. The TLR4 receptor is believed to be upregulated duringneuroimmune activation, which triggers the production of proinflammatorycytokines, leading to allodynia and hyperalgesia.

Because of the rarity of CRPS, little high-quality research has beenperformed to evaluate optimal management strategies. Currently, there isno FDA approved treatment for CRPS and it is an unmet medical need.Current treatment of CRPS includes physical and occupational therapy,pharmacotherapies, and interventional procedures. Pharmacologictreatments focus on traditional medicines for pain management, includingsteroids and opioids. Much of the current research is inconclusive as tothe efficacy of opioid treatment for CRPS.

SUMMARY

One example embodiment is directed to various methods of using low dosenaltrexone to treat chronic pain in a patient. The methods of using lowdose naltrexone to treat chronic pain includes administering to thepatient a first amount of naltrexone in an immediate-release agent and asecond amount of naltrexone in a modified-release agent.

There has thus been outlined, rather broadly, some of the embodiments ofthe present disclosure in order that the detailed description thereofmay be better understood, and in order that the present contribution tothe art may be better appreciated. There are additional embodiments thatwill be described hereinafter and that will form the subject matter ofthe claims appended hereto. In this respect, before explaining at leastone embodiment in detail, it is to be understood that the variousembodiments are not limited in its application to the details ofconstruction or to the arrangements of the components set forth in thefollowing description or illustrated in the drawings. Also, it is to beunderstood that the phraseology and terminology employed herein are forthe purpose of the description and should not be regarded as limiting.

To better understand the nature and advantages of the presentdisclosure, reference should be made to the following description andthe accompanying figures. It is to be understood, however, that each ofthe figures is provided for the purpose of illustration only and is notintended as a definition of the limits of the scope of the presentdisclosure. Also, as a general rule, and unless it is evidence to thecontrary from the description, where elements in different figures useidentical reference numbers, the elements are generally either identicalor at least similar in function or purpose.

BRIEF DESCRIPTION OF THE DRAWINGS

No figures are included with this application.

DETAILED DESCRIPTION A. Overview 1. Naltrexone

Naltrexone is approved for use in the treatment of alcohol use disorders(AUD) and other addictions, such as opioid dependence, e.g., a daily 50mg tablet or weekly 380 mg extended-release suspension. At standarddosage, naltrexone functions as an opioid antagonist having acompetitive binding affinity for μ-opioid receptors. As used herein,naltrexone includes (but is not limited to) naltrexone, its metabolites,including 6β-Naltrexol, enantiomers, including (+)-naloxone, isomers andracemic mixtures of same, in both free base and salt forms.

The disease state of CRPS involves inflammatory cytokines that circulatealong the patient's body. These inflammatory cytokines are known tocause some of the specific symptoms that result from CRPS includingedema, swelling, hypersensitivity to touch, allodynia, vasomotor andpseudo motor changes, and regulation of the inflammatory cytokinerelease.

Low-dose naltrexone is believed to down-regulate inflammatory cytokinerelease, which is important in patients who have complex regional painsyndrome (CRPS). Low-dose naltrexone's affect on cytokine release, inparticular, is beneficial to CRPS.

From a mechanistic standpoint, naltrexone is an antagonist to opioidreceptors and has the highest affinity to the mu-opioid receptor and, itis an antagonist of Toll-like receptors (TLR). TLRs lead to productionof pro-inflammatory cytokines when they are activated, so antagonizingTLRs decreases the activation of pro-inflammatory cytokines.Pro-inflammatory cytokines increase inflammation, and this is a hallmarkof the disease of CRPS because you see inflammation, hypersensitivity totouch, and allodynia which all occur as a result of CRPS. So by blockingthis, we are actually treating what likely is the mechanism of actionspecific to this particular disease state. This is counterintuitive asNaltrexone typically antagonizes opioids which are typically used totreat pain.

Naltrexone in higher doses functions as an opioid antagonist targetingthe mu and delta opioid receptors. Off-label uses of naltrexone haveexplored its use at lower doses through a different mechanism for thetreatment of inflammatory, rheumatological, and neurological conditions.These conditions include multiple sclerosis, fibromyalgia, Crohn'sdisease, chronic fatigue syndrome (CFS), and—more recently—CRPS. At thelow doses used for these conditions, naltrexone is thought to act as animmune modulator. Some speculate that this mechanism is caused byreduced neuroinflammation in the case of disorders like CFS. Evidencesuggests that, at low doses, naltrexone antagonizes TLR4 on activatedglial cells without the previously mentioned function as a mu opioidreceptor antagonist. Thus, low-dose naltrexone presents a promisingtherapeutic avenue for the treatment of CRPS, a condition in which TLR4upregulation is a primary pathway through attenuation of glial cellactivation and direct targeting of TLR4 activity.

In contrast with standard-dose naltrexone (i.e. 50 mg or higher),low-dose naltrexone is believed to exert its mechanism of action throughinteraction with and antagonism of Toll-like receptor 4 (TLR4). TLR4 hasbeen shown to be a key mediator of microglial cell activation, which hasbeen identified as a causal mechanism of neuropathic pain in CRPS.Microglial cell activation is associated with the release ofpro-inflammatory cytokines, reactive oxygen species, and prostaglandins,which amplify the inflammatory response. Another potential mechanism ofaction of low-dose naltrexone treatment is a paradoxical upregulation ofopioid signaling. Low-dose naltrexone leads to transient opioid receptorblockade, which triggers a positive feedback mechanism that increasesthe production of endogenous opioids (endogenous endorphins andenkephalins) and opioid signaling. Together, these mechanisms may workto alleviate pain associated with CRPS.

Not only does low-dose naltrexone treat the pain symptom of CRPS, but itcan also treat the disease process and disease cascades, since patientswho suffer from CRPS have not only increased neuro-inflammation andinflammatory cytokines, but also a decrease in endorphin and enkephalincirculation compared to the average patient. Increasing endogenousenkephalins and endorphins would help from a symptomatic standpoint.Blocking the Toll-like receptors would help the entire cascade of thedisease, decreasing the production of pro-inflammatory cytokines, andattenuation of the microglia and glial cells in the central andperipheral nervous system. It may actually treat the underlying diseasestate, which would be extremely beneficial to the patient.

2. Central Nervous System

Glial cell activation, inflammatory cytokines, and neuro-inflammationare hallmarks of the disease of CRPS. The toll-like receptor activity isvery important when looking at complex regional pain syndromespecifically.

In the central nervous system, low-dose naltrexone reduces toll-like TORsignaling in glial cell activation. Naltrexone is an antagonist of TOR.TOR activation leads to the production of NF-KB, which is aninflammatory signaling pathway. NF-KB is a tumor growth factor, but thisis also important in the inflammatory signaling pathway. This resultsprimarily in a reduction of inflammatory cytokines, but also reducesneuro-inflammation. This mechanism of action of low-dose naltrexone isparticularly important in patients experiencing CRPS. CRPS patientssuffer from severe debilitating pain, with even light touch or benignstimulation eliciting extreme amounts of pain. Microglial cells andglial cells are oftentimes involved in this pain-signaling pathway, andreduction in glial cell activation can help treat this pain syndrome.

3. Peripheral Nervous System

Low-dose naltrexone also has effects in the peripheral nervous systemwhere low-dose naltrexone can modulate T and B lymphocyte production. Inthe periphery nervous system, low-dose naltrexone can also reduceinterleukin 6, interleukin 12, and tumor necrosis factor alpha. This isvery important in patients who suffer from CRPS, specifically. Patientswho have CRPS often have an increase in inflammatory cytokines and mayoften note an increase in interleukin 6, interleukin 12, and tumornecrosis factor alpha. By reducing these inflammatory cytokines back towhat would be a more normal state, it is likely that we would be able totreat the actual disease state of complex regional pain syndrome.

4. Endogenous Enkephalins and Endorphins

Another important part of low-dose naltrexone is that it increasesendogenous enkephalins and endorphins which are the body's natural painkillers. For example, it is also noted that when taken at bedtime, theshort-acting low-dose naltrexone binds to receptors, leading to a briefblockade of opioid receptors between 2:00 a.m. and 4:00 a.m. Thisblockade is believed to up-regulate vital life elements of the body andcause an increase in endorphin and enkephalin production. This increasein endorphins and enkephalins causes a decrease in patient pain.

B. First Amount of Naltrexone

The first amount of naltrexone is administered to the patient directlyor within an immediate-release agent in a manner allowing for uptake ofthe first amount of naltrexone by the patient within a short period oftime (e.g. less than two hours in one example embodiment; less than 30minutes in another example embodiment). The first amount of naltrexonemay be selected based on the weight, sex or age of a given patient orvarious other factors. Various types of immediate-release agents may beused to administer the first amount of naltrexone.

In one example embodiment, the first amount of naltrexone ranges betweenapproximately 1.5 mg to 5 mg. In another example embodiment, the firstamount of naltrexone ranges between approximately 0.25 mg to 5 mg. Inanother example embodiment, the first amount of naltrexone rangesbetween approximately 0.25 mg to 2.00 mg. In another example embodiment,the first amount of naltrexone is approximately 1.5 mg. In anotherexample embodiment, the first amount of naltrexone is approximately 1.0mg. In another example embodiment, the first amount of naltrexone isapproximately 2 mg.

C. Second Amount of Naltrexone

The second amount of naltrexone is administered to the patient within amodified-release agent to allow uptake of the second amount ofnaltrexone to the patient over an extended period of time (e.g. in oneexample embodiment the extended period of time is two or more hours; inanother example embodiment the extended period of time is greater than30 minutes; in another example embodiment the extended period of time isbetween 30 minutes to two hours). In one example embodiment, the secondamount of naltrexone is administered to the patient after the firstamount of naltrexone has been administered to the patient. In anotherexample embodiment, the second amount of naltrexone is administered tothe patient while at least a portion of the first amount of naltrexoneis being administered to the patient. The second amount of naltrexonemay be selected based on the weight, sex or age of a given patient orvarious other factors.

In one example embodiment, the modified-release agent releases thesecond amount of naltrexone over a 30 minute to 24 hour period of time.In one example embodiment, the modified-release agent releases thesecond amount of naltrexone over a 30 minute to 4 hour period of time.In another example embodiment, the modified-release agent releases thesecond amount of naltrexone over a 30 minute to 1 hour period of time.In another example embodiment, the modified-release agent releases thesecond amount of naltrexone over a 30 minute to 3 hour period of time.

In one example embodiment, the second amount of naltrexone rangesbetween approximately 1.5 mg to 5 mg. In another example embodiment, thesecond amount of naltrexone ranges between approximately 1 mg to 5 mg.In another example embodiment, the second amount of naltrexone rangesbetween approximately 0.25 mg to 5 mg. In another example embodiment,the second amount of naltrexone is approximately 1.5 mg. In anotherexample embodiment, the second amount of naltrexone is approximately 1.0mg. In another example embodiment, the second amount of naltrexone isapproximately 2 mg.

In one embodiment, the modified-release agent is comprised of aslow-release agent. In another embodiment, the modified-release agent iscomprised of a controlled release agent. In another embodiment, themodified-release agent is comprised of a sustained release agent.Various types of modified-release agents may be used to administer thesecond amount of naltrexone.

D. Combined Total Amount of Naltrexone

In one example embodiment, the first amount of naltrexone and the secondamount of naltrexone combined equal a total amount of naltrexone that isa low-dosage of naltrexone. In another example embodiment, the firstamount of naltrexone and the second amount of naltrexone combined equala total amount of naltrexone that does not exceed 10 mg daily for apatient. In another example embodiment, the first amount of naltrexoneand the second amount of naltrexone combined equal a total amount ofnaltrexone that does not exceed 5 mg daily for a patient. In anotherexample embodiment, the total amount of naltrexone administered to thepatient daily ranges between approximately 1 mg to 5 mg. In anotherexample embodiment, the total amount of naltrexone administered to thepatient daily is approximately 4.5 mg. In another example embodiment,the total amount of naltrexone administered to the patient daily isapproximately 2 mg.

In another example embodiment, the total amount of naltrexoneadministered to the patient is approximately 2 mg per day forapproximately 4 weeks followed by 4 mg per day after the initial 4 weeksto treat the chronic pain disorder (e.g. CRPS). It can be appreciatedthat the initial period of time for treating the patient may exceed orbe less than 4 weeks.

In another example embodiment, the total amount of naltrexoneadministered to the patient is approximately 2 mg per day forapproximately 4 weeks followed by 4 mg per day after the initial 4 weeksto treat the chronic pain disorder (e.g. CRPS).

E. Methods and Systems of Administration to Patient

The first amount of naltrexone in the immediate-release agent and thesecond amount of naltrexone in a modified-release agent may beadministered to a patient in one of various methods such as orally (e.g.pill, liquid, suspension), transdermally (e.g. transdermal patch),topically, via injection, e.g., intravenous or intramuscular,inhalation, rectally, or the like.

In one example embodiment, the first amount of naltrexone and the secondamount of naltrexone are administered simultaneously via a pill ingestedby the patient. In another example embodiment, the first amount ofnaltrexone and the second amount of naltrexone are administered via abiphasic pill ingested by the patient. In one example embodiment of thenaltrexone delivered via a pill, the pill is comprised of a bilayer pillwith a first layer for the first amount of naltrexone and a second layerfor the second amount of naltrexone. In another example embodiment ofthe naltrexone delivered via a pill, the pill is comprised of an innerportion with the second amount of naltrexone within the modified-releaseagent surrounded by an outer layer with the first amount of naltrexonewithin the immediate-release agent. One benefit of using a bilayer pillto administer the first amount of naltrexone and the second amount ofnaltrexone independently is the reduction of lucid dreaming and otherside effects that can accompany high dosages of naltrexone.

F. Timing of Administration to Patient

In one example embodiment, the first amount of naltrexone in theimmediate-release agent and the second amount of naltrexone in amodified-release agent may be administered simultaneously to the patient(e.g. via a pill, liquid solution). In another example, embodiment, thefirst amount of naltrexone in the immediate-release agent and the secondamount of naltrexone in a modified-release agent may be administered tothe patient at separate times with the second amount of naltrexoneadministered shortly after the first amount of naltrexone isadministered to the patient.

In another example embodiment, the first amount of naltrexone and thesecond amount of naltrexone are administered to the patient inaccordance with the patient's sleep cycle. In on such embodiment, thefirst and second amounts of naltrexone are administered approximately 30minutes to 3 hours prior to the patient going to sleep. In anotherexample embodiment, the first amount of naltrexone and the second amountof naltrexone are administered to the patient just prior to the patientgoing to sleep. One believed benefit of administering the low-dosagenaltrexone within a few hours before the patient goes to sleep isbecause naltrexone works in part by stimulating endogenous endorphins(the body's natural pain killers) which are only produced by body insignificant quantities beginning approximately 3-4 hours into the sleepcycle.

In another example embodiment, the first amount of naltrexone and thesecond amount of naltrexone are administered to the patient in a mannerthat maintains a concentration of naltrexone in the patient'scirculatory system within an effective range over a twenty four hourperiod.

In one embodiment, a biphasic pill system is used to administer thenaltrexone to the patient with a lower dosage of naltrexone for a firstperiod of time followed by an increased dosage of naltrexone after thefirst period of time. In another example embodiment, a first totalamount of naltrexone is administered to the patient daily for a firstperiod of time and after the first period of time a second total amountof naltrexone is administered to the patient daily on a continuous basisto treat the chronic pain condition. In this example, the second totalamount of naltrexone is higher than the first total amount ofnaltrexone. In one variation of this example, the second total amount ofnaltrexone is higher than the first total amount of naltrexone by atleast two times. In another variation of this example, the first totalamount of naltrexone is substantially equal to the second total amountof naltrexone.

G. Example Embodiments 1. First Example Embodiment

One example method of using low-dose naltrexone to treat chronic paindisorders generally comprises administering to the patient a firstamount of naltrexone in an immediate-release agent and a second amountof naltrexone in a modified-release agent. Examples of chronic paindisorders include, but are not limited to, complex regional painsyndrome (CRPS), fibromyalgia, or neuropathic pain.

2. Second Example Embodiment

In a preferred example embodiment, a first total amount of naltrexone isadministered to the patient daily for an initial period of time (e.g.approximately 4 weeks) followed by a second total amount of naltrexoneper day after the initial period of time to treat the chronic paindisorder wherein the second total amount of naltrexone is higher thanthe first total amount of naltrexone. In the preferred embodiment, thenaltrexone may be administered to a patient in one of various methodssuch as orally (e.g. pill, multilayered pill, liquid, suspension),transdermally (e.g. transdermal patch), topically, via injection, e.g.,intravenous or intramuscular, inhalation, rectally, or the like.

In a variation of this preferred embodiment, the first total amount ofnaltrexone administered to the patient daily is comprised of the firstamount of naltrexone at approximately 1 mg and the second amount ofnaltrexone at approximately 1 mg for the initial period of time (e.g.approximately 4 weeks), and then the second total amount of naltrexoneadministered to the patient daily after the initial period of time iscomprised of the first amount of naltrexone at approximately 2 mg andthe second amount of naltrexone at approximately 2 mg to treat thechronic pain disorder.

In another variation of this preferred embodiment, the first totalamount of naltrexone administered to the patient daily in a multilayeredpill is comprised of the first amount of naltrexone at approximately 1mg in an immediate-release agent and the second amount of naltrexone atapproximately 1 mg in a modified-release agent for the initial period oftime (e.g. approximately 4 weeks), and then the second total amount ofnaltrexone administered to the patient daily after the initial period oftime is comprised of the first amount of naltrexone at approximately 2mg in an immediate-release agent and the second amount of naltrexone atapproximately 2 mg in a modified-release agent to treat the chronic paindisorder.

In this variation of this preferred embodiment, the first total amountof naltrexone of approximately 2 mg is administered daily to the patientdaily for the initial time period (e.g. 4 weeks) via a multilayered pillhaving an inner portion (or inner layer) with the second amount ofnaltrexone of approximately 1 mg within the modified-release agentsurrounded by an outer layer with the first amount of naltrexone ofapproximately 1 mg within the immediate-release agent. In furtherance ofthis variation of the preferred embodiment, the second total amount ofnaltrexone of approximately 4 mg is administered daily to the patientdaily after initial time period (e.g. after 4 weeks) via twomultilayered pills each having an inner portion (or inner layer) withthe second amount of naltrexone of approximately 1 mg within themodified-release agent surrounded by an outer layer with the firstamount of naltrexone of approximately 1 mg within the immediate-releaseagent. The modified-release agent may be a controlled release agent, asustained release agent or a slow-release agent.

3. Third Example Embodiment

In another preferred example embodiment, a method is disclosed ofadministering daily to the patient a first total amount of naltrexonefor an initial period of time, wherein the first total amount ofnaltrexone is less than 3 mg. In furtherance of this preferredembodiment, the method is disclosed of administering daily to thepatient a second total amount of naltrexone after the initial period oftime, wherein the second total amount of naltrexone is less than 5 mg,and wherein the second total amount of naltrexone is greater than thefirst total amount of naltrexone. In one variation of this preferredembodiment, the second total amount of naltrexone is approximately twotimes greater than the first total amount of naltrexone. In anothervariation of this preferred embodiment, the first total amount ofnaltrexone is comprised of a first amount of naltrexone in animmediate-release agent and a second amount of naltrexone in amodified-release agent, and wherein the second total amount ofnaltrexone is comprised of a third amount of naltrexone in animmediate-release agent and a fourth amount of naltrexone in amodified-release agent. In another variation of this preferredembodiment, the first amount of naltrexone is approximately 1 mg,wherein the second amount of naltrexone is approximately 1 mg, whereinthe third amount of naltrexone is approximately 2 mg, and wherein thefourth amount of naltrexone is approximately 2 mg. In another variationof this preferred embodiment, the first amount of naltrexone and thesecond amount of naltrexone are administered via a first pill ingestedby the patient, wherein the first pill is comprised an inner layer withthe second amount of naltrexone and an outer layer with the first amountof naltrexone, the third amount of naltrexone and the fourth amount ofnaltrexone are administered via a second pill ingested by the patient,wherein the second pill is comprised an inner layer with the fourthamount of naltrexone and an outer layer with the second amount ofnaltrexone.

4. Fourth Example Embodiment

In another preferred example embodiment of the method for treating achronic pain disorder in a patient, the method comprises administeringdaily to the patient a first pill having a first total amount ofnaltrexone for an initial period (e.g. approximately four weeks),wherein the first total amount of naltrexone is comprised of a firstamount of naltrexone in an immediate-release agent and a second amountof naltrexone in a modified-release agent, wherein the first amount ofnaltrexone is approximately 1 mg, wherein the second amount ofnaltrexone is approximately 1 mg, wherein the first amount of naltrexoneand the second amount of naltrexone are administered via a first pillingested by the patient, and wherein the first pill is comprised aninner layer with the second amount of naltrexone and an outer layer withthe first amount of naltrexone. In furtherance of this preferredembodiment, the method further comprises administering daily to thepatient a second pill having a second total amount of naltrexone afterthe initial period of time, wherein the second total amount ofnaltrexone is comprised of a third amount of naltrexone in animmediate-release agent and a fourth amount of naltrexone in amodified-release agent, wherein the third amount of naltrexone isapproximately 2 mg, wherein the fourth amount of naltrexone isapproximately 2 mg, wherein the third amount of naltrexone and thefourth amount of naltrexone are administered via at least one secondpill ingested by the patient, wherein the at least one second pill iscomprised an inner layer with the fourth amount of naltrexone and anouter layer with the third amount of naltrexone. One variation of thispreferred embodiment includes where the second total amount ofnaltrexone is administered to the patient via two pills ingested by thepill, wherein each of the two pills are comprised of half the fourthamount of naltrexone (e.g. approximately 1 mg) in the modified-releaseagent in an inner layer and half the third amount of naltrexone (e.g.approximately 1 mg) in the immediate-release agent of an outer layersurrounding the inner layer.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar to or equivalent to those described herein can be used in thepractice or testing of the various embodiments of the presentdisclosure, suitable methods and materials are described above. Allpatent applications, patents, and printed publications cited herein areincorporated herein by reference in their entireties, except for anydefinitions, subject matter disclaimers or disavowals, and except to theextent that the incorporated material is inconsistent with the expressdisclosure herein, in which case the language in this disclosurecontrols. The various embodiments of the present disclosure may beembodied in other specific forms without departing from the spirit oressential attributes thereof, and it is therefore desired that thevarious embodiments in the present disclosure be considered in allrespects as illustrative and not restrictive. Any headings utilizedwithin the description are for convenience only and have no legal orlimiting effect.

What is claimed is:
 1. A method for treatment of a chronic pain disorderin a patient, the method comprising administering to the patient a firstamount of naltrexone in an immediate-release agent and a second amountof naltrexone in a modified-release agent, wherein the first amount ofnaltrexone and the second amount of naltrexone combined equal a totalamount of naltrexone that does not exceed 5 mg.
 2. The method of claim1, wherein the first amount of naltrexone and the second amount ofnaltrexone are administered to the patient approximately 1 to 3 hoursprior to the patient going to sleep.
 3. The method of claim 1, whereinthe modified-release agent is a controlled release agent, a sustainedrelease agent or a slow-release agent.
 4. The method of claim 1, whereinthe second amount of naltrexone is only released to the patient afterthe first amount of naltrexone has been released to the patient, andwherein the modified-release agent releases the second amount ofnaltrexone over an extended period of time.
 5. The method of claim 1,wherein the modified-release agent releases the second amount ofnaltrexone over a 30 minute to 2 hour period of time.
 6. The method ofclaim 1, wherein the first amount of naltrexone is approximately 1 mgand wherein the second amount of naltrexone is approximately 1 mg. 7.The method of claim 1, wherein the total amount of naltrexone rangesbetween approximately 2 mg to 4 mg.
 8. The method of claim 1, whereinthe first amount of naltrexone and the second amount of naltrexone areadministered separately to the patient.
 9. The method of claim 1,wherein the first amount of naltrexone and the second amount ofnaltrexone are administered concurrently to the patient.
 10. The methodof claim 1, wherein the first amount of naltrexone and the second amountof naltrexone are administered to the patient via a transdermaladministration, a transdermal patch, a rectal administration, or orally.11. The method of claim 1, wherein the first amount of naltrexone andthe second amount of naltrexone are administered via a pill ingested bythe patient.
 12. The method of claim 1, wherein the first amount ofnaltrexone and the second amount of naltrexone are administered via apill ingested by the patient, wherein the pill is comprised an innerlayer with the second amount of naltrexone and an outer layer with thefirst amount of naltrexone.
 13. The method of claim 1, wherein the firstamount of naltrexone and the second amount of naltrexone areadministered via a pill ingested by the patient, wherein the pill iscomprised an inner layer with the second amount of naltrexone and anouter layer with the first amount of naltrexone, wherein the firstamount of naltrexone is approximately 1 mg, and wherein the secondamount of naltrexone is approximately 1 mg.
 14. A method for treatmentof a chronic pain disorder in a patient, the method comprising:administering daily to the patient a first total amount of naltrexonefor an initial period of time, wherein the first total amount ofnaltrexone is less than 3 mg; and administering daily to the patient asecond total amount of naltrexone after the initial period of time,wherein the second total amount of naltrexone is less than 5 mg, andwherein the second total amount of naltrexone is greater than the firsttotal amount of naltrexone.
 15. The method of claim 14, wherein thesecond total amount of naltrexone is approximately two times greaterthan the first total amount of naltrexone.
 16. The method of claim 14,wherein the first total amount of naltrexone is comprised of a firstamount of naltrexone in an immediate-release agent and a second amountof naltrexone in a modified-release agent, and wherein the second totalamount of naltrexone is comprised of a third amount of naltrexone in animmediate-release agent and a fourth amount of naltrexone in amodified-release agent.
 17. The method of claim 16, wherein the firstamount of naltrexone is approximately 1 mg, wherein the second amount ofnaltrexone is approximately 1 mg, wherein the third amount of naltrexoneis approximately 2 mg, and wherein the fourth amount of naltrexone isapproximately 2 mg.
 18. The method of claim 17, wherein the first amountof naltrexone and the second amount of naltrexone are administered via afirst pill ingested by the patient, wherein the first pill is comprisedan inner layer with the second amount of naltrexone and an outer layerwith the first amount of naltrexone.
 19. A method for treatment of achronic pain disorder in a patient, the method comprising: administeringdaily to the patient a first pill having a first total amount ofnaltrexone for an initial period, wherein the first total amount ofnaltrexone is comprised of a first amount of naltrexone in animmediate-release agent and a second amount of naltrexone in amodified-release agent, wherein the first amount of naltrexone isapproximately 1 mg, wherein the second amount of naltrexone isapproximately 1 mg, wherein the first amount of naltrexone and thesecond amount of naltrexone are administered via a first pill ingestedby the patient, and wherein the first pill is comprised an inner layerwith the second amount of naltrexone and an outer layer with the firstamount of naltrexone; and administering daily to the patient a secondpill having a second total amount of naltrexone after the initial periodof time, wherein the second total amount of naltrexone is comprised of athird amount of naltrexone in an immediate-release agent and a fourthamount of naltrexone in a modified-release agent, wherein the thirdamount of naltrexone is approximately 2 mg, wherein the fourth amount ofnaltrexone is approximately 2 mg, wherein the third amount of naltrexoneand the fourth amount of naltrexone are administered via at least onesecond pill ingested by the patient, and wherein the at least one secondpill is comprised an inner layer with the fourth amount of naltrexoneand an outer layer with the third amount of naltrexone.
 20. The methodof claim 19, wherein the initial period is comprised of approximatelyfour weeks.